日本毒性学会学術年会
第51回日本毒性学会学術年会
セッションID: S8-4
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シンポジウム8: 日韓合同シンポジウム:オルガネラ毒性と代謝疾患
全身性の糖代謝異常へのDrp1-filamin複合体形成の関与
*Yuri KATOKohei ARIYOSHITsukasa SHIMAUCHIAkiyuki NISHIMURAXinya MISang Geon KIMYasuo MORIMotohiro NISHIDA
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Diabetes is a chronic metabolic disorder that affects nearly 10% of adult people worldwide. It is characterized by high levels of blood glucose, which can lead to a range of complications, such as cardiovascular disease, neuropathy, and retinopathy. Recently, mitochondrial quality control has been highlighted as a potential therapeutic target for treating diabetes and its complications. We previously reported that mitochondrial hyperfission by forming a protein complex between dynamin-related protein (Drp) 1 and filamin A (FLNa), mediates chronic heart failure and cilnidipine, developed as an L/N-type Ca2+ channel blocker, improves heart failure by inhibiting Drp1-FLNa protein complex. Therefore, we investigated whether cilnidipine improves hyperglycemia of various diabetic model mice.

Cilnidipine treatment improved systemic hyperglycemia and mitochondrial morphological abnormalities in STZ-exposed mice, without lowering blood pressure. In contrast, cilnidipine failed to improve hyperglycemia of ob/ob mice, by suppressing insulin secretion. Therefore, we have identified a Ca2+ channel-insensitive cilnidipine derivative (1,4-DHP) that does not inhibit insulin release. 1,4-DHP improved hyperglycemia and mitochondria morphology abnormality in ob/ob mice fed high-fat diet. These results suggested that maintaining mitochondrial quality by inhibition of Drp1-FLNa becomes a new strategy for diabetes treatment to treat diabetes and diabetic complications.

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